Distal Sensory Peripheral Neuropathy is emerging as the commonest neurological complication of HIV infection which is often debilitating. Yet, it has remained largely ignored by researchers. The pathogenesis of this entity is obscure and there is no available treatment. Both HIV infection and the nucleoside reverse transcriptase inhibitor (NRTI) drugs cause a sensory peripheral neuropathy that is clinically indistinguishable. Available evidence suggests that the neurodegenerative changes in the cell bodies of the sensory fibers residing in the dorsal root ganglia are likely the major target of the NRTIs and of the toxic substances released from HIV infected non-neuronal cells. We have established cultures from human and mouse dorsal root ganglia. Preliminary data from our laboratory invokes oxidative stress as an important mechanism involved in HIV and VRTI mediated neurotoxicity. This supports other mounting evidence that oxidative pathways play an important role in HIV pathogenesis. We propose to determine the effect of neurotoxic HIV proteins (gp120 and Tat), HIV infection (lymphotropic and macrophage tropic strains) and NRTIs on DRG neurons. We will also determine the combined effects of HrV or HIV proteins and NRTIs. Several markers of oxidative stress and mitochondrial dysfunction will be monitored in the cultured DRG neurons. Additionally, morphological changes and immunostaining patterns in the neurons and the neuritis will be determined. We will characterize the subpopulations of cells that are particularly vulnerable to these neurotoxic substances. Finally, a panel of novel antioxidants, with potential clinical applicability will be screened for their ability to protect against this neurotoxicity.